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Japanese trial of patients who were intolerant to likely to have a sustained response after 12 weeks of or ineligible for interferon, 10 patients discontinued daclatasvir and sofosbuvir compared to those who did because of elevations in liver enzymes and one not have cirrhosis. This combination was not assessed because of myasthenia gravis.6 When peginterferon in patients with genotype 1 disease and cirrhosis. The and ribavirin were added to daclatasvir and combination of daclatasvir and asunaprevir (with or asunaprevir, 18 patients discontinued. The most without peginterferon and ribavirin) was effective in a common reasons were rash, malaise, neutropenia and range of patients with genotype 1 or 4 infection. vertigo (2 cases of each).7 Daclatasvir regimens were generally well tolerated but Cardiac arrhythmias, including severe bradycardia, prescribers should be mindful of adverse reactions to have been reported in patients taking amiodarone other drugs in the treatment regimen. As daclatasvir with daclatasvir and sofosbuvir, so close monitoring is is metabolised by CYP3A4, there are numerous recommended with this combination. drug interactions that need to be considered. Most Daclatasvir should not be used in pregnancy. In animal importantly, concomitant use of strong CYP3A4 studies, it has been shown to cross the placenta, inducers is contraindicated as this may reduce the and maternal and embryofetal toxicity have been efficacy of daclatasvir. observed at high doses. Contraception should be T T manufacturer provided additional useful used during treatment and for five weeks afterwards. information Daclatasvir is also excreted in milk and breastfeeding REFERENCES † is not recommended. 1. Thompson A, Holmes J. Treating hepatitis C – what’s new. The safety and efficacy of daclatasvir in people Aust Prescr 2015. Epub ahead of print. who are co-infected with hepatitis B have not been 2. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, et al.; AI444040 Study Group. established as these patients were generally excluded Daclatasvir plus sofosbuvir for previously treated or untreated from the trials. chronic HCV infection. N Engl J Med 2014;370:211-21. 3. Nelson DR, Cooper JN, Lalezari JP, Lawitz E, Pockros PJ, Resistance to daclatasvir can occur. If patients Gitlin N, et al.; ALLY-3 Study Team. All-oral 12-week experience an increase in viral RNA during treatment, treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III the regimen should be discontinued. study. Hepatology 2015;61:1127-35. 4. Wyles DL, Ruane PJ, Sulkowski MS, Dieterich D, Drug interactions Luetkemeyer A, Morgan TR, et al.; ALLY-2 Investigators. Daclatasvir plus sofosbuvir for HCV in patients coinfected Daclatasvir is mainly metabolised by cytochrome with HIV-1. N Engl J Med 2015;373:714-25. 5. Manns M, Pol S, Jacobson IM, Marcellin P, Gordon SC, P450 (CYP) 3A4. It is contraindicated in combination Peng CY, et al.; HALLMARK-DUAL Study Team. All‑oral with strong inducers of CYP3A4 (e.g. phenytoin, daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study. carbamazepine, rifampicin, dexamethasone and Lancet 2014;384:1597-605. St John’s wort), as these drugs may lower daclatasvir 6. Kumada H, Suzuki Y, Ikeda K, Toyota J, Karino Y, Chayama K, et al. Daclatasvir plus asunaprevir for chronic HCV genotype exposure. The daily daclatasvir dose should be 1b infection. Hepatology 2014;59:2083-91. increased to 90 mg with moderate CYP3A4 7. Jensen D, Sherman KE, Hézode C, Pol S, Zeuzem S, de Ledinghen V, et al.; HALLMARK-QUAD Study Team. inducers. Conversely, the dose should be reduced Daclatasvir and asunaprevir plus peginterferon alfa and to 30 mg per day with strong CYP3A4 inhibitors ribavirin in HCV genotype 1 or 4 non-responders. J Hepatol 2015;63:30-7. (e.g. clarithromycin, boceprevir, telaprevir, atazanavir, ritonavir, ketoconazole). First published online 1 October 2015 As daclatasvir inhibits P-glycoprotein, co-administered digoxin and other P-glycoprotein substrates with a Ledipasvir with sofosbuvir narrow therapeutic index, such as dabigatran, should be used with caution. Care is also urged with the Approved indication: hepatitis C statins as rosuvastatin concentrations are increased Harvoni (Gilead) with daclatasvir. 90 mg/400 mg tablets Conclusion Australian Medicines Handbook section 5.5 In general, daclatasvir-containing regimens were Sofosbuvir (Aust Prescr 2014;37:177-8) is a nucleotide very effective at clearing hepatitis C virus in patients analogue antiviral drug that is used in combination with chronic disease. This included those who had with other drugs to treat chronic hepatitis C. As the not adequately responded to previous treatments effectiveness of regimens containing interferon can be and patients who were co-infected with HIV. With limited by adverse effects, there is interest in studying the daclatasvir and sofosbuvir combination, adding other drugs to use in combination with sofosbuvir. ribavirin did not seem to give further benefit. Patients Ledipasvir is an antiviral drug aimed at a protein with genotype 3 infection who had cirrhosis were less (NS5A) in the hepatitis C virus. As this protein is
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involved in viral replication, ledipasvir will reduce The ION-3 trial assessed the efficacy of a shorter the amount of virus in infected patients. Ledipasvir treatment regimen in previously untreated patients is rapidly absorbed. As the solubility of ledipasvir is without cirrhosis. It randomised 647 patients to take the pH-dependent, antacids, proton pump inhibitors and combination of ledipasvir and sofosbuvir, with or without
H2-receptor antagonists can decrease absorption. ribavirin, for eight weeks, or the combination alone for Ledipasvir is minimally metabolised with most of the 12 weeks. There was a sustained virological response dose being excreted unchanged in the faeces. The in 94% of the patients who took the combination for median half-life is 47 hours. No dose adjustment is eight weeks (93% with ribavirin) compared with 95% required in patients with hepatic impairment. who took it for 12 weeks.3 An eight-week regimen The fixed-dose combination of ledipasvir and can therefore be considered in previously untreated sofosbuvir has mainly been studied in patients patients without cirrhosis who have pre-treatment viral with genotype 1 infection. Its approval is based on RNA concentrations below 6 million IU/mL. open‑label clinical trials which assessed the virological ION-4 was an open-labelled study involving 335 response (see Table). A sustained virological patients who were infected with hepatitis C virus response was defined as a viral RNA in the patient’s and HIV. Using a 12-week regimen, a sustained serum below 25 IU/mL 12 weeks after the end of response against hepatitis C was achieved by 96% of treatment. However, the World Health Organization the patients. Results were similar irrespective of the has previously considered a sustained response to treatments used for HIV in the trial, and whether or be the absence of viral RNA six months after the end not the patients had cirrhosis.4 of treatment. Less than 1% of the patients treated with ledipasvir In ION-1, 865 previously untreated patients were and sofosbuvir had to stop treatment because of randomised to take the combination, with or without adverse effects. Without ribavirin, the most frequent ribavirin, in either 12- or 24-week regimens. There adverse events with the combination were fatigue, was a sustained viral response in 97–99% of the headache, nausea and insomnia. There are no human patients. This response was achieved by 94–100% data in pregnancy and lactation, but the combination of the patients who had cirrhosis (16% of the trial had no effect on fetal development in animal studies. participants).1 Drug interactions can occur with one or both The ION-2 trial used the same four treatment components of the combination, so it is best to check regimens as ION-1, but studied 440 patients who had the product information before prescribing. Its efficacy not responded to other treatments for genotype 1 could be reduced by inducers of P-glycoprotein infections. Approximately 20% of these patients had such as rifampicin and St John’s wort. There is a cirrhosis. Twelve weeks after completing 12 weeks potentially fatal interaction with amiodarone. Other of treatment, there was a virological response of interactions include digoxin, antiepileptic drugs, and 94–96%. In patients who were treated for 24 weeks a statins particularly rosuvastatin. There is no known viral RNA below 25 IU/mL was achieved in 99%. The interaction with oral contraception. response rate was significantly lower in patients with Resistance to ledipasvir can develop during treatment. cirrhosis who were treated for 12 weeks compared This should be considered in patients who do not with 24 weeks (82–86% vs 100%).2 have a sustained virological response.
Table Efficacy of ledipasvir and sofosbuvir in hepatitis C
Trial Patients Sustained virological response for patients taking 12-week regimens ‡
Ledipasvir/sofosbuvir Ledipasvir/sofosbuvir plus ribavirin ION-11 865 previously 99% (211/214) 97% (211/217) untreated patients ION-22 440 previously 94% (102/109) 96% (107/111) treated patients ION-33 647 previously 95% (206/216) - untreated patients without cirrhosis ION-44 335 patients 96% (322/335) - coinfected with HIV
‡ Primary outcome was the proportion of patients who had no quantifiable RNA in their sera 12 weeks after treatment
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A once-daily, interferon-free treatment, which in Ponatinib is also indicated for those with Ph-positive most cases only needs to be taken for 12 weeks, acute lymphoblastic leukaemia who are resistant or that has very high efficacy is an advance. While intolerant to dasatinib, cannot be given imatinib or further research is needed for other genotypes, have the T315I mutation. the combination of ledipasvir and sofosbuvir is The approval of ponatinib is primarily based on a probably the treatment of choice for genotype 1 phase II, single-arm trial. The study enrolled 449 hepatitis C infection in 2015. However, until similar people with chronic myeloid leukaemia (n=417) or 5 antiviral drugs arrive, cure comes with a high cost. Ph-positive acute lymphoblastic leukaemia (n=32). The Pharmaceutical Benefits Advisory Committee Almost all of the patients had experienced treatment estimates that the cost of treatment in Australia will failure with imatinib.1 exceed $3 billion over five years.6 Patients were started on ponatinib 45 mg once a day. T manufacturer provided the product information Those with chronic myeloid leukaemia were grouped into cohorts according to whether they had chronic-, REFERENCES *† accelerated- or blast-phase disease. The primary end 1. Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al.; ION-1 Investigators. Ledipasvir and sofosbuvir point for those with chronic-phase disease was a for untreated HCV genotype 1 infection. N Engl J Med major cytogenetic response (when the proportion of 2014;370:1889-98. Ph-positive white blood cells has fallen to 35% or less) 2. Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al.; ION-2 Investigators. Ledipasvir and within the first 12 months. For patients with accelerated- sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014;370:1483-93. and blast-phase chronic myeloid leukaemia or 3. Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Ph-positive acute lymphoblastic leukaemia, the Lawitz E, et al.; ION-3 Investigators. Ledipasvir and primary end point was a major haematological sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014;370:1879-88. response (normal number of white blood cells or no 4. Naggie S, Cooper C, Saag M, Workowski K, Ruane P, evidence of leukaemia) in the first six months.1 Towner WJ, et al.; ION-4 Investigators. Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1. Just over half of the patients with chronic- and N Engl J Med 2015;373:705-13. 5. Hoofnagle JH, Sherker AH. Therapy for hepatitis C--the costs accelerated-phase chronic myeloid leukaemia of success. N Engl J Med 2014;370:1552-3. responded to treatment. Response rates were lower 6. Pharmaceutical Benefits Scheme. March 2015 PBAC in people with blast-phase chronic myeloid leukaemia Meeting – positive recommendations. Canberra: Australian Government Department of Health; 2015. and Ph-positive acute lymphoblastic leukaemia www.pbs.gov.au/info/industry/listing/elements/pbac- meetings/pbac-outcomes/2015-03 [cited 2015 Oct 2] (see Table). Pre-specified subgroup analyses revealed that fewer previous treatments, younger age and First published online 14 October 2015 shorter duration between diagnosis and treatment tended to predict a better response to ponatinib.1 Ponatinib Adverse reactions were very common in the trial with 67% of patients having at least one dose Approved indication: chronic myeloid leukaemia, interruption because of an adverse event. The most acute lymphoblastic leukaemia common treatment-related events (any grade) were Iclusig (Ariad Pharmaceuticals) thrombocytopenia (37% of patients), rash (34%), 15 and 45 mg film-coated tablets dry skin (32%), vascular occlusion (23%), abdominal Australian Medicines Handbook section 14.2.3 pain (22%), neutropenia (19%) and anaemia (13%).1 Infections occurred in over half of the people who Along with imatinib (Aust Prescr 2001;24:129), received ponatinib – these were serious in 20% of dasatinib (Aust Prescr 2007;30:50-5) and nilotinib (Aust Prescr 2008;31:49-55), ponatinib is a tyrosine cases and some were fatal. kinase inhibitor for patients who have leukaemia Serious adverse events (grade 3 or 4) included with the Philadelphia chromosome (Ph). This pancreatitis (5%), abdominal pain (2%), increased chromosome results in an abnormal tyrosine kinase lipase (2%), thrombocytopenia (2%), diarrhoea (1%), that causes uncontrolled growth of malignant cells. fever (1%), myocardial infarction (1%), anaemia (1%), Almost all patients with chronic myeloid leukaemia neutropenia (1%), febrile neutropenia (1%) and and approximately 20–25% of those with acute pancytopenia (1%).1 Thrombocytopenia was the most lymphoblastic leukaemia have the chromosome. common reason for treatment interruption. Ponatinib is indicated for patients with chronic During the study, 18/449 patients died. Five deaths myeloid leukaemia who are resistant or intolerant to were thought to be related to treatment and were at least two previous tyrosine kinase inhibitors, or a result of pneumonia, fungal pneumonia, gastric have the T315I mutation. Patients with this mutation haemorrhage, acute myocardial infarction and are resistant to imatinib, dasatinib and nilotinib. cardiac arrest. Other deaths deemed unrelated to
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